The pharmacological action of snake venom is one of the most complex phenomena is nature. In the past 20 years many unusual chemical constituents of venoms have been isolated and their physiological properties have been investigated.
The mortality rate from snake bites in the temperature and tropical zones of the world is in the neighborhood of 25,000 to 30,000 per year. Treatment of snake bites is a difficult problem which requires very special skills. Research is continuing on the production of improved as well as new methods for neutralizing the toxins of the snake venoms.
It is now well established that venomous snakes are not susceptable to large amounts of their own or closely related venoms. This observation led to the inquiry as to whether any protection was afforded by fractions of snake blood or snake plasma against the actions of the venom.
One of the most prominent pathologic changes produced by vipers and pit viper snake venoms is hemorrhage. It was proposed by Philpot and Deutsch, (Inhibition and Activation of Venom Proteases, Biochimica et Biophysica Acta, Vol. 29, pp. 524-530, 1956) that the hemorrhage was in part due to the presence of unique and powerful proteolytic enzymes in the venoms.
Deutsch and Dinitz (Journal of Biological Chemistry, Vol. 216 p. 17, 1955) demonstrated that the proteolytic activities of fifteen crotalid venoms of the genera Crotalus and Bothrops all were capable of liberating bradykinin from a serum globulin fraction and that all venoms digested fibrinogen far more rapidly than fibrin.
A simplified mechanism of crotalid venoms leading to hemorrhage and death can be illustrated in the attached FIGURE.
In this scheme it will be observed that the venom protease, shown schematically in the upper block, has at least two actions. The arrow pointing to the right indicates that plasma fibrinogen is fragmented resulting in poor clotting. The action of protease as shown with the arrow pointing to the left is liberation of bradykinin from a plasma globulin. Drastic elevation of bradykinin levels results in broncho-constriction and vasodilation. A second powerful hydrolytic enzyme in the crotalid venom is hyaluronidase shown in the lower block. This enzyme depolymerizes the mucopolysaccharides which hold the vascular cells together, thereby making the capillary bed permeable and resulting in hemorrhage. The consequence of generalized and extensive bleeding is death due to hypovolemic shock.
The prevention of hemorrhage and neutralization of the lethal effects of pit viper venoms by certain snake sera was demonstrated by Philpot and R. G. Smith as far back as 1950. (Proc. Soc. Exptl. Biol. Med., Vol. 74, p. 521, 1950)
Further work by Philpot and others has shown that a protein fraction is present in the sera of snakes belonging to the genus Crotalidae and Colubridae which protects mice from the lethal effect of 5.times.LD.sub.50 of crotalid venoms injected intra-peritoneally. Fractionation of the sera by ammonium sulfate precipitation and molecular sieving on Sephadex indicated that the neutralizing components of snake sera are contained in proteins of the molecular weight in the range of 70,000 to 90,000 Daltons. See U.S. Pat. No. 4,012,502 issued Mar. 15, 1977, the disclosure of which is hereby incorporated by reference. The most pronounced effect of the purified serum proteins there described was the ability to inhibit venom protease activity.
Although the venom protease resembles trypsin in its action, it is not inhibited by known trypsin inhibitors or by Trasylol, a known kallekrein inhibitor.
The inhibition of the venom protease by snake serum proteins is probably a deliberate event of nature which provides the snake with a self-protective mechanism, which is analogous to the trypsin-antitrypsin protective mechanism in mammals.